Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome

Marije E.C. Meuwissen (1) , Rachel Schot (1) , Sofija Buta (2) , Grétel Oudesluijs (1) , Sigrid Tinschert (3, 4) , Scott Speer (2) , Zhi Li (5, 6) , Leontine van Unen (1) , Daphne Heijsman (1) , Tobias Goldmann (7) , Maarten Lequin (1) , Johan Kros (1) , Wendy Stam (1) , Mark Hermann (2) , Rob Willemsen (1) , Rutger W.W. Brouwer (1) , Wilfred F.J. van Ijcken (1) , Marta Martin-Fernandez (2) , Irenaeus de Coo (1) , Jeroen Dudink (1) , Femke A.T. de Vries (1) , Aida Bertoli Avella (1) , Marco Prinz (8) , Yanick Crow (9, 10) , Frans Verheijen (1) , Sandra Pellegrini (6, 5) , Dusan Bogunovic (2) , Grazia M.S. Mancini (1)

1 Erasmus MC - Erasmus University Medical Center [Rotterdam]
2 MSSM - Icahn School of Medicine at Mount Sinai [New York]
3 Medical Faculty Carl Gustav Carus
4 IMU - Innsbruck Medical University = Medizinische Universität Innsbruck
5 Signalisation des Cytokines
6 Signalisation des Cytokines - Cytokine Signaling
7 institute of neuropathology
8 University of Freiburg [Freiburg]
9 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
10 MCGM - Manchester Centre for Genomic Medicine [Manchester, UK]

Pseudo-TORCH syndrome (PTS) is characterized by microcephaly, enlarged ventricles, cerebral calcification, and, occasionally, by systemic features at birth resembling the sequelae of congenital infection but in the absence of an infectious agent. Genetic defects resulting in activation of type 1 interferon (IFN) responses have been documented to cause Aicardi-Goutières syndrome, which is a cause of PTS. Ubiquitin-specific peptidase 18 (USP18) is a key negative regulator of type I IFN signaling. In this study, we identified loss-of-function recessive mutations of USP18 in five PTS patients from two unrelated families. Ex vivo brain autopsy material demonstrated innate immune inflammation with calcification and polymicrogyria. In vitro, patient fibroblasts displayed severely enhanced IFN-induced inflammation, which was completely rescued by lentiviral transduction of USP18. These findings add USP18 deficiency to the list of genetic disorders collectively termed type I interferonopathies. Moreover, USP18 deficiency represents the first genetic disorder of PTS caused by dysregulation of the response to type I IFNs. Therapeutically, this places USP18 as a promising target not only for genetic but also acquired IFN-mediated CNS disorders.

Domaines: Génétique; Immunologie

Marije E.C. Meuwissen, Rachel Schot, Sofija Buta, Grétel Oudesluijs, Sigrid Tinschert, et al.. Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome. Journal of Experimental Medicine, 2016, 213 (7), pp.1163-1174. ⟨10.1084/jem.20151529⟩. ⟨pasteur-02070980⟩